JP2004522696A - Methods of treating schizophrenia and related psychiatric disorders and the use of erythropoietin or erythropoietin derivatives for the treatment of schizophrenia and related psychiatric disorders - Google Patents
Methods of treating schizophrenia and related psychiatric disorders and the use of erythropoietin or erythropoietin derivatives for the treatment of schizophrenia and related psychiatric disorders Download PDFInfo
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Abstract
エリスロポエチンを哺乳動物に投与する、哺乳動物の精神分裂病および関連する精神病の治療及び/又は予防の方法。A method for treating and / or preventing schizophrenia and related psychiatric disorders in a mammal, which comprises administering erythropoietin to the mammal.
Description
【0001】
本発明は、「精神分裂病」のもとに下記に包含される精神分裂病および関連の精神病の治療法、およびエリスロポイエチンを使用する上記の意味における精神分裂病の治療の手段に関する。
【0002】
上記の定義の意味における精神分裂病の病因論および病原論は現在まで未知である。事実、遺伝の影響の重要な役割については意見の一致があるが、例えば神経外傷、薬物消費のような疾病の突発に影響があると思われる一連の多分関連のある補助因子は公知である。特に、この疾病で病因論的に役割を演じる分子的および細胞的な機構も未知である。従って、精神分裂病のための本当に良い動物のモデルは現在まで作られていない。現在利用できる動物モデルは疾病の部分的な状況を包含するに過ぎない。
【0003】
従って、本発明の目的は精神分裂病および関連の精神病を治療する方法および精神分裂病および関連の精神病を治療する手段を利用できるようにすることである。
【0004】
この目的は請求項1記載の方法によって、また請求項8または17記載の使用によって達成される。本発明による方法および本発明による使用の有利な展開は、それぞれの従属請求項に示される。
【0005】
この場合、精神分裂病とは、実際の精神分裂病および関連の精神病と理解される。治療としては、すでに発生している症状の場合での治療だけでなく、例えば神経外傷、精神外傷などで高い遺伝因子を持つ人々の場合のように特に危険度のある人々の場合での予防的な使用も考慮される。
【0006】
この場合、精神分裂病において提案される医療上の神経保護は、一般に完全に新しい治療的および予防的な出発点である。これは、疾病の最初のエピソードの途中において認識的/精神的機能の劇的な損傷が起こり、それは少なくとも部分的に可逆的であり、むしろ一定のまたは進行性の少ない水準でその後のエピソードで一般に横ばいになるという疫学専門家および臨床医によって再三確認された知見を考慮に入れている。ここに、神経保護療法の方法の一貫した使用は、特に精神病の最初のエピソードにおいて、症状阻止の神経遮断薬に関連して「追加(アドオン)療法」としても介在する。特に危険度のある人々へのエリスロポイエチンの予防的な使用は、本発明によっても提案される。
【0007】
エリスロポイエチンは、「EPO」と略記もされるが、身体中に天然に存在する分子量34,000ダルトンの糖蛋白である(W.ジェルクマン「エリスロポイエチン:構造、製造の制御、および機能」、フィジオロジカル・レビュー、1992年、72巻、449−489ページ)。それは赤血球の生産のための必須の成長因子であり、すでに1977年に最初に単離された。
【0008】
エリスロポイエチンは、計画された手術の前にかなり多量の自己血液を得るために、腎性貧血を持つ患者の場合に腎臓透析に長年の間しばしば臨床使用されてきたし、またスポーツ薬としても新聞の見出しを飾った。
【0009】
エリスロポイエチンは、この場合非常に良く耐容性を示すことがわかった。特に、ポリグロブリンによるしばしば治療的に要求される造血の刺激およびめったに見られない動脈性筋緊張亢進は、関連の副作用として言及されるべきである。両方の作用は、主に長期のエリスロポイエチンの投与の後で予想されるべきものである。これらは、必要な場合比較的簡単に医薬治療または瀉血で治癒する。エリスロポイエチンの場合、不耐性反応または過敏症反応はめったにない。
【0010】
分子量約34,000ダルトンのかなり大きい蛋白質として、エリスロポイエチンは一般に知られるように血液脳関門を突破することはできない。しかし、エリスロポイエチンの直接の脳室内投与、すなわち脳組織内へのエリスロポイエチンの直接の注入はヒトにおいては普通排除される。それは感染や出血のような一時的な脳室ドレナージの設定および維持に含まれる危険性のためである。
【0011】
本発明による方法および本発明によるエリスロポイエチンの使用のための有利な出発点は、精神分裂病の場合、血液脳関門の障害が一般に精神病の急性期において起こり、それは血液中を循環するエリスロポイエチンの脳への急速な交差を許す。
【0012】
本発明は、今や精神病の急性期の場合において、血液脳関門がエリスロポイエチンを通すことが発見されたということで、有利に進行する。従って、例えば腸管外ならびに血管中,鼻内、吸入、特に静脈内,皮下および/または筋肉内(例えデポー式)のエリスロポイエチンの全身的末梢投与はそれでも成功する。
【0013】
長期の治療の場合に、エリスロポイエチンの投与の緩慢な効果は、(週200、000IUまでの投与による)定常的な高血液水準で、そのままの血液脳関門にかかわらず脳への血液脳関門を通じてのエリスロポイエチンの交差が起こる間は起こる。
【0014】
精神病の急性期の場合における脳へのエリスロポイエチンのこの意外な交差によって、または長期の治療中のエリスロポイエチンの極めて高い血中水準のために、エリスロポイエチンの極めて高い血中水準のために、エリスロポイエチンは精神分裂病の病因論に潜在的に含まれるすべての三つの機構に影響を与えるために使用でき、その機構は神経細胞の機能不全をもたらす。これらは断片化、神経細胞の代謝障害およびシナプスの連結/軸索の発生である。
【0015】
精神分裂病の場合の医療的な神経保護は一般に完全に新しい治療的および予防的方策であることが要約として確立できる。
【0016】
本発明による方法の二三の例およびその結果を下記に示す。
【0017】
すなわち、図1Aおよび図1Bには、精神分裂病患者の脳の断片の免疫組織化学的検査が示されている。
【0018】
亜急性疾病期(第一または第二の発現)にある三人の精神分裂病患者および2人の健全な患者についての試験系列において、個々の患者にそれぞれ40,000i.Uのインジウム−11l−エリスロポイエチン、合計120−185MBqを一度に静脈内に投与した。つぎに、単光子放出コンピュータ断層撮影(SPECTー写真 )を行ったが、この写真は放射能で標識したエリスロポイエチンの投与の4.18〜21時間または42〜45時間後に撮影された。
【0019】
下記の表1には、「脳の平均衝動含量/頭蓋冠の骨髄の平均衝動含量」の商が示されている。
【0020】
【表1】
【0021】
精神分裂病をもつ三人の患者1ないし3では、三つの時点すべてにおいて放射能で標識したエリスロポイエチンの明確な脳内蓄積が見られ、この蓄積は健全な実験者1および2より患者1ないし3において全般に高い。放射性エリスロポイエチンのこの多量蓄積は表1に示す商から直ちにわかる。
【0022】
従って、エリスロポイエチンは健康な人々の場合よりも精神病の(亜)急性期の精神分裂病患者の場合において、より強く血液脳関門を突破することが先ず示された。さらに、対応する高投与量でそのままの血液脳関門をもつ健康な人々の場合でも、エリスロポイエチンはこれを突破することができることが先ず確立された。従って、急性疾病期が過ぎても、すなわちやはりそのままの血液脳関門の場合でも、精神分裂病患者の長期の治療は神経保護的な追加(アドオン)療法として十分に高い脳内水準をもたらすことができる。
【0023】
この場合、エリスロポイエチンは精神分裂病の病因論に潜在的に含まれる三つの機構のすべてに影響を与えることができ、その機構は神経細胞の機能不全をもたらす;
a)断片化、
b)神経細胞の代謝的障害、
c)シナプスの連結/軸索の発生。
【0024】
精神分裂病患者の脳中でのエリスロポイエチンの神経保護の効果のための必須条件は、神経細胞上の特定のエリスロポイエチン受容体へのその結合である。これらは、本発明のために行われた免疫組織化学的研究で初めて発見された。
【0025】
図1は、精神分裂病患者の海馬状隆起(死後の脳)からの組織学的断片を示し、この場合、免疫組織化学によってエリスロポイエチン受容体(EPOR;赤に着色、左の画像、図1A)が、また二重蛍光法によって、それの位置が神経細胞の上に探索できた(EPOR;橙色に着色、NeuN=神経細胞マーカー、緑色に着色、右の画像、図1B)。緑色蛍光の神経細胞は赤色蛍光のEPOR抗体でも標識され、その結果、図1Bに橙色の着色が生じることがすぐにわかる。精神分裂病患者の脳の神経細胞がエリスロポイエチン受容体に対して免疫反応性を持つことがこの研究で先ず確立された。
【0026】
図1Aおよび図1Bのために、断片はヘモ‐DE(ドイツ、シュべルテ、フィッシャー・サイエンティフィク)中で脱パラフィンされ、5分間三回の洗浄工程を行い,それらは順に量を減らしたアルコール中で再水和し、蒸留水で洗い、クエン酸緩衝液中で沸騰させ、トリス緩衝の食塩溶液(TBS)中で洗い、室温で0.05%ツイーン‐20/TBS中10%の遮断血清で培養し、つづいて2%ヤギ血清/PBS中で、ポリクローナル野兎抗ヒトEPOR抗体(1:200、C−20、ドイツ、ハイデルベルグ、サンタクルツ・バイオテクノロジー)で4℃で一夜培養した。0.05%ツイーン‐20/TBSで洗ったあと、断片は、テキサスレッド標識されたヤギ抗野兎抗体(1:100、米国、カリフォルニア、バーリンゲーム、ベクター・ラボラトリーズ・インコーポレーテッド)で加湿室中で(30分間)培養した。0.05%ツイーン‐20/TBSで洗ったあと、断片は、2%ウマ血清/PBS中で、モノクローナルマウス‐抗神経細胞核(NeuN)抗体(1:500、米国、カリフォルニア、テメクラ、ケムコン・インターナショナル・インコーポレーテッド)で+4℃で(24h)培養し、0.05%ツイーン‐20/TBSで洗い、フルオレセインで標識したウマー抗マウス抗体(FITC)(1:100、ベクター)で加湿室中で30分間培養した。つぎに、断片は0.05%ツイーン‐20/TBSおよびTBSで洗い、最後にベクタシールド(ベクター)蛍光培地中に包埋した。
【図面の簡単な説明】
【図1】
図1A及び図1Bには、精神分裂症患者の脳切断面における免疫組織化学検査が示されている。[0001]
The present invention relates to a method of treating schizophrenia and related psychiatric disorders, encompassed below under "Schizophrenia", and to means of treating schizophrenia in the above sense using erythropoietin.
[0002]
The etiology and etiology of schizophrenia in the sense of the above definitions is unknown to date. In fact, while there is consensus on the important role of genetic effects, a range of possibly relevant cofactors are known that may affect the onset of diseases such as neurotrauma, drug consumption. In particular, the molecular and cellular mechanisms that play a pathogenic role in this disease are also unknown. Thus, no really good animal model for schizophrenia has been created to date. Currently available animal models only cover a partial context of the disease.
[0003]
Accordingly, it is an object of the present invention to make available methods and methods for treating schizophrenia and related psychiatric disorders.
[0004]
This object is achieved by a method according to claim 1 and by a use according to claim 8 or 17. Advantageous developments of the method according to the invention and the use according to the invention are indicated in the respective dependent claims.
[0005]
In this case, schizophrenia is understood as actual schizophrenia and related psychiatric disorders. Treatment may include treatment of pre-existing symptoms, as well as prophylactic treatment of people at high risk, such as those with high genetic factors such as neurotrauma or trauma. Use is also considered.
[0006]
In this case, the proposed medical neuroprotection in schizophrenia is generally a completely new therapeutic and prophylactic starting point. This results in a dramatic impairment of cognitive / mental functioning in the middle of the first episode of the disease, which is at least partially reversible, rather at a constant or less progressive level in subsequent episodes generally It takes into account findings that have been repeatedly confirmed by epidemiologists and clinicians to level off. Here, the consistent use of methods of neuroprotective therapy also mediates as "add-on" therapies, especially in the first episode of psychosis, in connection with neuroleptics for symptomatic arrest. The prophylactic use of erythropoietin, especially for people at risk, is also proposed by the present invention.
[0007]
Erythropoietin, also abbreviated as "EPO", is a glycoprotein naturally occurring in the body with a molecular weight of 34,000 daltons (W. Jerkumann, "Erythropoietin: Structure, Control of Production, and Function"). Physiological Review, 1992, 72, 449-489). It is an essential growth factor for the production of red blood cells and was first isolated already in 1977.
[0008]
Erythropoietin has often been used clinically for renal dialysis in patients with renal anemia for many years to obtain significant amounts of autologous blood prior to planned surgery, and has also been used as a sports drug in the newspaper. The headline was decorated.
[0009]
Erythropoietin was found to be very well tolerated in this case. In particular, the often therapeutically required stimulation of hematopoiesis and rare arterial hypertonia by polyglobulins should be mentioned as relevant side effects. Both effects are to be expected mainly after long-term administration of erythropoietin. They are relatively easily cured with pharmacotherapy or phlebotomy when needed. In the case of erythropoietin, intolerance or hypersensitivity reactions are rare.
[0010]
As a fairly large protein with a molecular weight of about 34,000 daltons, erythropoietin cannot break through the blood-brain barrier, as is commonly known. However, direct intraventricular administration of erythropoietin, ie, direct infusion of erythropoietin into brain tissue, is usually ruled out in humans. It is because of the risks involved in setting up and maintaining temporary ventricular drainage, such as infection and bleeding.
[0011]
An advantageous starting point for the method according to the invention and for the use of erythropoietin according to the invention is that in the case of schizophrenia, impairment of the blood-brain barrier generally occurs in the acute phase of psychosis, which circulates in the blood. Allow rapid crossing of Etin into the brain.
[0012]
The present invention advantageously proceeds with the discovery that the blood-brain barrier is permeable to erythropoietin, now in the acute phase of psychosis. Thus, systemic peripheral administration of erythropoietin, for example parenterally and intravascularly, intranasally, by inhalation, in particular intravenously, subcutaneously and / or intramuscularly (eg depot), is still successful.
[0013]
In the case of long-term treatment, the slow effect of the administration of erythropoietin is that at a steady high blood level (by administration up to 200,000 IU / week), the blood-brain barrier to the brain irrespective of the intact blood-brain barrier It occurs while the crossing of erythropoietin through occurs.
[0014]
Due to this surprising crossing of erythropoietin into the brain in the case of acute phase of psychosis, or due to very high blood levels of erythropoietin during long-term treatment, due to very high blood levels of erythropoietin In addition, erythropoietin can be used to affect all three mechanisms potentially involved in the pathogenesis of schizophrenia, which lead to neuronal dysfunction. These are fragmentation, impaired metabolism of neurons and the development of synaptic connections / axons.
[0015]
It can be established in summary that medical neuroprotection in the case of schizophrenia is generally a completely new therapeutic and prophylactic strategy.
[0016]
A few examples of the method according to the invention and the results are given below.
[0017]
Thus, FIGS. 1A and 1B show an immunohistochemical examination of a fragment of the brain of a schizophrenic patient.
[0018]
In a test series of three schizophrenic patients and two healthy patients in a subacute disease stage (first or second episode), each patient had 40,000 i.d. U indium-111-erythropoietin, a total of 120-185 MBq, was administered intravenously at one time. Next, single-photon emission computed tomography (SPECT-photographs) were performed, which were taken 4.18-21 hours or 42-45 hours after administration of radiolabeled erythropoietin.
[0019]
In Table 1 below, the quotient of "mean brain impulse content / mean calvarial bone marrow impulse content" is shown.
[0020]
[Table 1]
[0021]
In three patients with schizophrenia 1 to 3, there was a clear brain accumulation of radiolabeled erythropoietin at all three time points, and this accumulation was higher than in healthy experimenters 1 and 2 in patient 1 In general, it is high in 3 to 3. This high accumulation of radioactive erythropoietin is immediately apparent from the quotients shown in Table 1.
[0022]
Thus, erythropoietin was first shown to break through the blood-brain barrier more strongly in schizophrenic patients in the (sub) acute phase of psychosis than in healthy people. In addition, it was first established that erythropoietin can break through even the healthy blood-brain barrier at correspondingly high doses. Thus, even after the acute stage of disease, that is, the blood-brain barrier as well, long-term treatment of schizophrenic patients can result in sufficiently high brain levels as neuroprotective add-on therapies. it can.
[0023]
In this case, erythropoietin can affect all three mechanisms potentially involved in the pathogenesis of schizophrenia, which lead to neuronal dysfunction;
a) fragmentation,
b) metabolic disorders of nerve cells,
c) Synaptic connection / axon development.
[0024]
A prerequisite for the neuroprotective effect of erythropoietin in the brain of schizophrenic patients is its binding to specific erythropoietin receptors on nerve cells. These were first discovered in immunohistochemical studies performed for the present invention.
[0025]
FIG. 1 shows a histological fragment from the hippocampus of a schizophrenic patient (post-mortem brain), in which erythropoietin receptor (EPOR; colored red, left image, figure by immunohistochemistry) 1A), but its location could also be probed on the nerve cells by double fluorescence (EPOR; orange colored, NeuN = neuronal marker, green colored, right image, FIG. 1B). It can be readily seen that the green fluorescent neurons are also labeled with the red fluorescent EPOR antibody, resulting in orange coloring in FIG. 1B. This study first established that neurons in the brain of schizophrenic patients were immunoreactive for erythropoietin receptors.
[0026]
For FIGS. 1A and 1B, the fragments were deparaffinized in Hemo-DE (Fischer Scientific, Schwerte, Germany) and subjected to three washing steps for 5 minutes, which were in turn reduced in volume. Rehydrate in alcohol, wash with distilled water, boil in citrate buffer, wash in Tris-buffered saline (TBS), block at room temperature with 10% in 0.05% Tween-20 / TBS The cells were cultured in serum and then overnight at 4 ° C. in 2% goat serum / PBS with a polyclonal rabbit anti-human EPOR antibody (1: 200, C-20, Santa Cruz Biotechnology, Heidelberg, Germany). After washing with 0.05% Tween-20 / TBS, the fragments were digested with a Texas Red-labeled goat anti-rabbit antibody (1: 100, Vector Laboratories, Burlingame, Calif., USA, Vector Laboratories, Inc.) in a humidified chamber. (30 minutes). After washing with 0.05% Tween-20 / TBS, the fragments were cloned in 2% horse serum / PBS in a monoclonal mouse-anti-neuronal nucleus (NeuN) antibody (1: 500, Chemcon International, Temecula, CA, USA, USA). (Incorporated) at + 4 ° C. (24 h), washed with 0.05% Tween-20 / TBS, and fluorescein-labeled umer anti-mouse antibody (FITC) (1: 100, vector) in a humidified chamber for 30 h. Incubated for minutes. Next, the fragments were washed with 0.05% Tween-20 / TBS and TBS and finally embedded in VectorShield (Vector) fluorescent medium.
[Brief description of the drawings]
FIG.
1A and 1B show an immunohistochemical examination on a brain cut surface of a schizophrenic patient.
Claims (25)
Applications Claiming Priority (2)
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DE10043457A DE10043457A1 (en) | 2000-09-04 | 2000-09-04 | Processes for treating schizophrenia and related psychoses, and using erythropoietin or erythropoietin derivatives to treat schizophrenia and related psychoses |
PCT/EP2001/010198 WO2002020031A2 (en) | 2000-09-04 | 2001-09-04 | Use of erythropoietin and the derivatives of the same for treating schizophrenia and related psychoses |
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JP2004522696A true JP2004522696A (en) | 2004-07-29 |
JP2004522696A5 JP2004522696A5 (en) | 2008-09-18 |
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JP2002524514A Pending JP2004522696A (en) | 2000-09-04 | 2001-09-04 | Methods of treating schizophrenia and related psychiatric disorders and the use of erythropoietin or erythropoietin derivatives for the treatment of schizophrenia and related psychiatric disorders |
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US (1) | US20040009912A1 (en) |
EP (1) | EP1315515B1 (en) |
JP (1) | JP2004522696A (en) |
AU (1) | AU2002213878A1 (en) |
CY (1) | CY1107287T1 (en) |
DE (2) | DE10043457A1 (en) |
DK (1) | DK1315515T3 (en) |
ES (1) | ES2296819T3 (en) |
PT (1) | PT1315515E (en) |
WO (1) | WO2002020031A2 (en) |
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US9988427B2 (en) | 2005-05-13 | 2018-06-05 | Charite Universitaetsmedizen-Berlin | Erythropoietin variants |
EP1736481A1 (en) | 2005-05-13 | 2006-12-27 | Charite Universitätsmedizin-Berlin | Erythropoietin variants |
US20070072795A1 (en) * | 2005-09-28 | 2007-03-29 | Anton Haselbeck | Treatment of neurodegenerative disorders |
RU2484836C2 (en) * | 2011-09-21 | 2013-06-20 | Александр Иванович Воронов | Method of treating schizophrenia |
Citations (2)
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JPH0592928A (en) * | 1991-09-30 | 1993-04-16 | Snow Brand Milk Prod Co Ltd | Therapeutic agent for dysmnesia |
WO2000035475A2 (en) * | 1998-12-14 | 2000-06-22 | Hannelore Ehrenreich | Method for the treatment of cerebral ischaemia and use of erythropoietin or erythropoietin derivatives for the treatment of cerebral ischaemia |
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US5416071A (en) * | 1991-03-12 | 1995-05-16 | Takeda Chemical Industries, Ltd. | Water-soluble composition for sustained-release containing epo and hyaluronic acid |
EP1171147A4 (en) * | 1999-04-13 | 2003-05-14 | Kenneth S Warren Inst Inc | Modulation of excitable tissue function by peripherally administered erythropoietin |
-
2000
- 2000-09-04 DE DE10043457A patent/DE10043457A1/en not_active Ceased
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2001
- 2001-09-04 JP JP2002524514A patent/JP2004522696A/en active Pending
- 2001-09-04 PT PT01982244T patent/PT1315515E/en unknown
- 2001-09-04 WO PCT/EP2001/010198 patent/WO2002020031A2/en active IP Right Grant
- 2001-09-04 EP EP01982244A patent/EP1315515B1/en not_active Expired - Lifetime
- 2001-09-04 AU AU2002213878A patent/AU2002213878A1/en not_active Abandoned
- 2001-09-04 DE DE50113300T patent/DE50113300D1/en not_active Expired - Lifetime
- 2001-09-04 DK DK01982244T patent/DK1315515T3/en active
- 2001-09-04 ES ES01982244T patent/ES2296819T3/en not_active Expired - Lifetime
- 2001-09-04 US US10/363,617 patent/US20040009912A1/en not_active Abandoned
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0592928A (en) * | 1991-09-30 | 1993-04-16 | Snow Brand Milk Prod Co Ltd | Therapeutic agent for dysmnesia |
WO2000035475A2 (en) * | 1998-12-14 | 2000-06-22 | Hannelore Ehrenreich | Method for the treatment of cerebral ischaemia and use of erythropoietin or erythropoietin derivatives for the treatment of cerebral ischaemia |
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DE10043457A1 (en) | 2002-03-28 |
WO2002020031A3 (en) | 2002-08-01 |
EP1315515A2 (en) | 2003-06-04 |
DK1315515T3 (en) | 2008-04-14 |
PT1315515E (en) | 2008-03-03 |
US20040009912A1 (en) | 2004-01-15 |
ES2296819T3 (en) | 2008-05-01 |
CY1107287T1 (en) | 2012-11-21 |
DE50113300D1 (en) | 2008-01-03 |
WO2002020031A2 (en) | 2002-03-14 |
EP1315515B1 (en) | 2007-11-21 |
AU2002213878A1 (en) | 2002-03-22 |
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